Development of a novel adjuvant strategy enabled by modulation of the physical properties of fungal mannans

PROJECT SUMMARY Vaccines represent a highly effective public health measure to protect individuals from infectious diseases. Many vaccines work by inducing antigen-specific antibodies that neutralize the pathogen or its products and promote their clearance. Vaccines based on protein antigens usually require the addition of adjuvants to enhance potency, breadth and duration of the antigen-specific adaptive immune response. Adjuvants promote vaccine antigen immunogenicity by activating receptors of the innate immune system called pattern-recognition receptors (PRRs) and/or modulating antigen pharmacokinetics. Aluminum salts are the most common adjuvants in FDA- approved vaccines. Recently, vaccines including adjuvants that target specific PRRs, in particular toll-like receptor (TLR)4 and TLR9, have also been approved by the FDA, paving the way for the development of molecularly defined adjuvants. Investigating the potential of additional PRRs as adjuvant targets is of paramount important to expand our vaccine toolbox and probe how different modalities of innate immune cell activation impact the adaptive immune response. Here, we propose to use the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein as a model antigen to test a new adjuvant formulation that contains fungal ligands that target the PRR Dectin-2. Our preliminary results show that mannans (fungal cell wall polysaccharides isolated from Candia albicans) alone or formulated with aluminum hydroxide enhance the immunogenicity of pre-fusion stabilized, Spike trimers in mouse models of immunization. In particular, mannan formulations, compared to aluminum hydroxide only, induce an early increase in anti-Spike antibody levels, potentiate the induction of SARS-CoV-2 neutralizing antibodies, broaden the Spike epitopes that are targeted and favor the switch towards immunoglobulin subclasses associated with higher effector functions and reduced risk of vaccine-associated enhanced respiratory disease (VAERD). Here we hypothesize that mannans formulated with alumOH induce a potent and durable adaptive immune response to SARS-CoV-2 Spike by inducing specific innate immune pathways and activation programs. By combining detailed immunogenicity and mechanistic analyses, our proposal will define a novel adjuvant formulation for SARS-CoV-2 Spike and potentially other viral glycoproteins as well as shed new light on the biology of Dectin-2.